U.S. Pat. Nos. 5,690,907, 5,780,010 and 5,958,371, the disclosures of which are incorporated herein by reference, describe biotinylated lipid-encapsulated perfluorocarbon nanoparticles which are useful for the delivery of radionuclides, and magnetic resonance imaging agents to specific locations through a biotin-avidin system. Bioactive agents may also be included. In this approach, the target location is coupled to a target-specific ligand which is also coupled to biotin. Avidin is then employed to bridge the now biotinylated target with biotin derivatized nanoparticles contained in an emulsion. Included among the targets are blood clots; however, these blood clots are first labeled with antifibrin antibodies to which biotin is then bound. No direct targeting of blood clots with ligands specific for such clots is disclosed.
This is in contrast to the compositions of the present invention wherein a ligand specific for thromboses is directly coupled, initially, to the nanoparticles in the emulsion. Thus, the emulsion, when administered, is target-specific by virtue of bearing the target-specific ligand at its surface.
Fluorochemical emulsions with specification binding moieties have been described in U.S. Pat. No. 5,401,634 for use as labels in in vitro analytical procedures. However, in vivo uses, for example, for acoustic imaging, drug delivery or delivery of imaging agents or nuclides is not contemplated. In addition, consistent with the failure to envision in vivo use, no modification of these particles for binding to thromboses is mentioned.
Others have described drug delivery using particulate supports which differ from the nanoparticles of the present invention. For example, PCT publication WO95/03829 describes oil emulsions where the drug is dispersed or solubilized inside an oil droplet and the oil droplet is targeted to a specific location by means of a ligand. U.S. Pat. No. 5,542,935 describes site-specific drug delivery using gas-filled perfluorocarbon microspheres. The drug delivery is accomplished by permitting the microspheres to home to the target and then effecting their rupture. Low boiling perfluoro compounds are used to form the particles so that the gas bubbles can form.
In contrast to the compositions described above, the compositions of the invention are ligand-bearing liquid emulsions based on high boiling perfluorocarbon liquids. The compositions of the invention provide facile means to deliver materials contained in their surface to blood clots.
An article reporting the work of the present inventors, Flacke, S., et al., Circulation (2001) 104:1280–1285 appeared in September of 2001 and described molecular imaging of thrombus using nanoparticles formulated with GD-DTPA-BOA. The particles were covalently coupled to antifibrin monoclonal antibody and used to obtain magnetic resonance images of blood clots.
The present invention expands the concept set forth in this article and provides nanoparticles which target blood clots specifically and which may provide, in addition to magnetic resonance imaging agents, means for acoustic imaging, therapeutic agents, and radionuclides.